Methylation of KRAS by SETD7 promotes KRAS degradation in non-small cell lung cancer

Cheng-Yao Chiang; Songqing Fan; Hongmei Zheng; Wenjun Guo; Zehan Zheng; Yihua Sun; Chuanqi Zhong; Juan Zeng; Shuaihu Li; Min Zhang; Tian Xiao; Duo Zheng

doi:10.1016/j.celrep.2023.113003

Methylation of KRAS by SETD7 promotes KRAS degradation in non-small cell lung cancer

Cell Rep. 2023 Sep 26;42(9):113003. doi: 10.1016/j.celrep.2023.113003. Epub 2023 Sep 8.

Authors

Cheng-Yao Chiang¹, Songqing Fan², Hongmei Zheng², Wenjun Guo¹, Zehan Zheng¹, Yihua Sun³, Chuanqi Zhong⁴, Juan Zeng⁵, Shuaihu Li¹, Min Zhang¹, Tian Xiao⁶, Duo Zheng⁷

Affiliations

¹ Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, International Cancer Center, Department of Cell Biology and Genetics, Shenzhen University Medical School, Thoracic Surgery Department of the First Affiliated Hospital, Shenzhen University, Shenzhen 518055, China.
² Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
³ Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
⁴ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
⁵ School of Biomedical Engineering, Guangdong Medical University, Dongguan, Guangdong 523808, China.
⁶ Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, International Cancer Center, Department of Cell Biology and Genetics, Shenzhen University Medical School, Thoracic Surgery Department of the First Affiliated Hospital, Shenzhen University, Shenzhen 518055, China. Electronic address: txiao@szu.edu.cn.
⁷ Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, International Cancer Center, Department of Cell Biology and Genetics, Shenzhen University Medical School, Thoracic Surgery Department of the First Affiliated Hospital, Shenzhen University, Shenzhen 518055, China. Electronic address: dzheng@szu.edu.cn.

PMID: 37682707
DOI: 10.1016/j.celrep.2023.113003

Abstract

Oncogenic KRAS mutations are a key driver for initiation and progression in non-small cell lung cancer (NSCLC). However, how post-translational modifications (PTMs) of KRAS, especially methylation, modify KRAS activity remain largely unclear. Here, we show that SET domain containing histone lysine methyltransferase 7 (SETD7) interacts with KRAS and methylates KRAS at lysines 182 and 184. SETD7-mediated methylation of KRAS leads to degradation of KRAS and attenuation of the RAS/MEK/ERK signaling cascade, endowing SETD7 with a potent tumor-suppressive role in NSCLC, both in vitro and in vivo. Mechanistically, RABGEF1, a ubiquitin E3 ligase of KRAS, is recruited and promotes KRAS degradation in a K182/K184 methylation-dependent manner. Notably, SETD7 is inversely correlated with KRAS at the protein level in clinical NSCLC tissues. Low SETD7 or RABGEF1 expression is associated with poor prognosis in lung adenocarcinoma patients. Altogether, our results define a tumor-suppressive function of SETD7 that operates via modulating KRAS methylation and degradation.

Keywords: CP: Cancer; CP: Molecular biology; KRAS; RABGEF1; SETD7; lysine methylation; non-small cell lung cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Non-Small-Cell Lung* / pathology
Guanine Nucleotide Exchange Factors / metabolism
Histone-Lysine N-Methyltransferase / genetics
Histone-Lysine N-Methyltransferase / metabolism
Humans
Lung Neoplasms* / pathology
Methylation
Protein Processing, Post-Translational
Proto-Oncogene Proteins p21(ras) / genetics
Proto-Oncogene Proteins p21(ras) / metabolism

Substances

Proto-Oncogene Proteins p21(ras)
Histone-Lysine N-Methyltransferase
KRAS protein, human
SETD7 protein, human
RABGEF1 protein, human
Guanine Nucleotide Exchange Factors